8-81681502-C-T

Position:

• chr8-81681502-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005536.4(IMPA1):​c.59G>A​(p.Gly20Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IMPA1 NM_005536.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.51

Genes affected

IMPA1 (HGNC:6050): (inositol monophosphatase 1) This gene encodes an enzyme that dephosphorylates myo-inositol monophosphate to generate free myo-inositol, a precursor of phosphatidylinositol, and is therefore an important modulator of intracellular signal transduction via the production of the second messengers myoinositol 1,4,5-trisphosphate and diacylglycerol. This enzyme can also use myo-inositol-1,3-diphosphate, myo-inositol-1,4-diphosphate, scyllo-inositol-phosphate, glucose-1-phosphate, glucose-6-phosphate, fructose-1-phosphate, beta-glycerophosphate, and 2'-AMP as substrates. This enzyme shows magnesium-dependent phosphatase activity and is inhibited by therapeutic concentrations of lithium. Inhibition of inositol monophosphate hydroylosis and subsequent depletion of inositol for phosphatidylinositol synthesis may explain the anti-manic and anti-depressive effects of lithium administered to treat bipolar disorder. Alternative splicing results in multiple transcript variants encoding distinct isoforms. A pseudogene of this gene is also present on chromosome 8q21.13. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IMPA1	NM_005536.4	c.59G>A	p.Gly20Glu	missense_variant	2/9	ENST00000256108.10	NP_005527.1
IMPA1	NM_001144878.2	c.236G>A	p.Gly79Glu	missense_variant	3/10		NP_001138350.1
IMPA1	NM_001144879.2	c.59G>A	p.Gly20Glu	missense_variant	2/8		NP_001138351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IMPA1	ENST00000256108.10	c.59G>A	p.Gly20Glu	missense_variant	2/9	1	NM_005536.4	ENSP00000256108	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2023

The c.236G>A (p.G79E) alteration is located in exon 3 (coding exon 2) of the IMPA1 gene. This alteration results from a G to A substitution at nucleotide position 236, causing the glycine (G) at amino acid position 79 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.;.;T;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.79	T;T;T;T;T;T
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Uncertain	0.094	D
MutationAssessor	Pathogenic	3.4	M;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.6	D;D;D;D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;.;.;.
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.86
MutPred		0.91		Loss of catalytic residue at A19 (P = 0.1218);Loss of catalytic residue at A19 (P = 0.1218);.;Loss of catalytic residue at A19 (P = 0.1218);.;Loss of catalytic residue at A19 (P = 0.1218);
MVP		0.81
MPC		0.63
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.99
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-82593737;